Compounds of use in the treatment of epilepsy, seizure, and electroconvulsive disorders

ABSTRACT

The present invention provides pharmaceutical preparations and the uses thereof for preventing and/or treating seizures and other electroconvulsive disorders by administering a pharmaceutically effective amount of a therapeutic compound having the following formula (I):  
                 
 
     Embodiments include administering an effective amount of 4,4′-thiodianiline, 4,4′-diaminobenzophenone, 4,4′-methylenedianiline, 4,4′-diaminodiphenyl ether, or (3-aminophenyl)-(4-aminophenyl) amine, an analog, or a pharmaceutically accepted salt or complex thereof to a mammal in need of treatment or prevention of epilepsy, seizure, or other electroconvulsive disorder.

RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional PatentApplication No. 60/348,366 filed Jan. 16, 2002, which is incorporatedherein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to bridged dianilino compounds andpharmaceutical compositions and method of use thereof for the preventionand treatment of epilepsies, seizures, and other electroconvulsivedisorders. Specifically, this invention relates to the use of4,4′-thiodianiline, 4,4′-diaminobenzophenone, 4,4′-methylenedianiline,4,4′-diaminodiphenyl ether, or (3-aminophenyl)-(4-aminophenyl) amine andrelated compounds, and preparations thereof, for the prevention,palliation and/or treatment of seizures, conduction disturbances andelectroconvulsive disorders of all types, manifestations and origins, inhumans and in animals.

BACKGROUND OF THE INVENTION

[0003] Epilepsy is a general term describing a group of central nervoussystem disorders that are characterized by recurrent seizures that arethe outward manifestation of excessive and/or hyper-synchronous abnormalelectrical activity of neurons of the cerebral cortex and other regionsof the brain. This abnormal electrical activity can be manifested asmotor, convulsion, sensory, autonomic, or psychic symptoms.

[0004] Epilepsy affects millions of people worldwide, and over 2.5million individuals in the United States. For the purposes of clinicalassessment, it is useful to classify patients according to the type ofseizure the patient experiences. As described in The PharmacologicalBasis of Therapeutics, 9^(th) Ed. (McGraw-Hill) [1], there are twoclasses of seizures: partial seizures and generalized seizures. Partialseizures consist of focal and local seizures. Partial seizures arefurther classified as simple partial seizures, complex partial seizuresand partial seizures secondarily generalized. Generalized seizures areclassified as convulsive and nonconvulsive seizures. They are furtherclassified as absence (previously referred to as ‘petit mal’) seizures,atypical absence seizures, myoclonic seizures, clonic seizures, tonicseizures, tonic-clonic seizures, and atonic seizures.

[0005] Hundreds of epileptic syndromes have been defined as disorderscharacterized by specific symptoms that include epileptic seizures.These include, but are not limited to, absence epilepsy, psychomotorepilepsy, temporal lobe epilepsy, frontal lobe epilepsy, occipital lobeepilepsy, parietal lobe epilepsy, Lennox-Gastaut syndrome, Rasmussen'sencephalitis, childhood absence epilepsy, Ramsay Hunt Syndrome type II,benign epilepsy syndrome, benign infantile encephalopathy, benignneonatal convulsions, early myoclonic encephalopathy, progressiveepilepsy and infantile epilepsy. A patient may suffer from anycombination of different types of seizures. Partial seizures are themost common, and account for approximately 60% of all seizure types.Regardless of the type of epilepsy, seizures significantly limit theautonomy of the patient.

[0006] It is believed that the characteristic seizures of epilepsy arecaused by the disordered, synchronous, and rhythmic firing of brainneurons. The neurons can fire at up to four times their normal rate. Asa result, epileptic seizures are an overstimulation of the normalneuronal processes that control brain function.

[0007] Anti-epileptic drugs are available for treating epilepsies, butthese agents have a number of shortcomings. For instance, the agents areoften poorly soluble in aqueous and biological fluids or are extremelyhygroscopic. Of even greater importance is that patients often becomerefractory to a drug over time. In addition, many anti-epileptic agentscause unwanted side effects, neurotoxicities, and drug interactions.Even while being treated with one or a combination of the anti-epilepticdrugs currently in clinical use, 30% of epileptic patients stillexperience seizures. As more anti-epileptic drugs are developed, theclinician will have expanded pharmaceutical options when designing aneffective treatment protocol for each patient. Accordingly, a continuingneed exists for pharmaceutical compositions that treat or preventepilepsy and its associated symptoms with minimal side effects.

[0008] After experimentation and investigation, it has been discoveredthat oral and intraperitoneal administration of a therapeutic compoundcomprising formula (I) below to mice and rats resulted in profound andreproducible anticonvulsant or antiepileptic activity in animal modes ofseizure disorders. It has further been discovered that these compoundsdo not show acute neurotoxic effects at the levels required for atherapeutic response.

SUMMARY OF THE INVENTION

[0009] An advantage and object of the present invention is apharmaceutical composition useful for the treatment, prevention and/oramelioration of disorders related to and including epilepsy, seizure,and other electroconvulsive disorders.

[0010] According to the present invention, the foregoing objects andadvantages are achieved in part by a therapeutic compound, includingresolved enantiomers, diastereoisomers, tautomers, salts, solvates andpolymorphic forms thereof, having the following formula (I):

[0011] wherein R₁, R₂, R₃, and R₄, are each independently selected fromthe group consisting of hydrogen, hydroxy, amino, phenyl, a substitutedor unsubstituted C₁₋₁₀ alkyl, C₃₋₁₀ branched alkyl, a substituted orunsubstituted C₃₋₈ cycloalkyl, a substituted or unsubstituted arylalkyl,a substituted or unsubstituted C₁₋₁₀ alkoxyl and a substituted orunsubstituted C₁₋₁₀ acyl; and X is selected from the group consisting of—O—, —S—, —N(H)—, —Se—, —Si—, —CH═CH—, —C≡C—, —N═N—, —N═CH—, —CH═N—,—C(S)—, —N(H)S(O)—, —N(H)SO₂—, —N(H)O—, —N(H)S—, —S(O)—, —SO₂—, —PO₄—,—Si(O)—, —C(O)—, —CH₂—, —CF₂—, and a covalent bond.

[0012] Another object of the present invention is a method of treating,ameliorating, or preventing epilepsy, seizure or electroconvulsivedisorders in a subject in need thereof. In an embodiment of the presentinvention, the method comprises administering an effective amount of4,4′-thiodianiline, 4,4′-diaminobenzophenone, 4,4′-methylenedianiline,4,4′-diaminodiphenyl ether, or (3-aminophenyl)-(4-aminophenyl) amine, ora pharmaceutically acceptable salt or complex thereof to a subject inneed of treatment, amelioration, or prevention of such disorders.

[0013] Further according to the invention, the foregoing objects andadvantages for the treatment or prevention of electroconvulsivedisorders are achieved by administering a pharmaceutical compositioncomprising an effective amount of the therapeutic compound to mammals inan admixture with a pharmaceutically acceptable carrier, adjuvant orvehicle.

[0014] Still further according to the invention, the foregoing objectsand advantages for the treatment or prevention of electroconvulsivedisorders are achieved by administering an effective amount of4,4′-thiodianiline, 4,4′-diaminodiphenyl ether,4,4′-diaminobenzophenone, 4,4′-methylenedianiline, or(3-aminophenyl)-(4-aminophenyl) amine, or a pharmaceutically acceptablesalt or complex thereof and in a pharmaceutically accepted carrier,adjuvant or vehicle.

[0015] Embodiments of the present invention include a pharmaceuticalcomposition comprising a dose of about 0.1 mg/kg to 300 mg/kg of4,4′-thiodianiline, 4,4′-diaminobenzophenone, 4,4′-methylenedianiline,4,4′-diaminodiphenyl ether, or (3-aminophenyl)-(4-aminophenyl) amine orthe equivalent of its pharmaceutically acceptable salt.

[0016] Additional advantages of the present invention will becomereadily apparent to those skilled in the art from this followingdetailed description. As will be realized, the invention is capable ofother and different embodiments, and its several details are capable ofmodifications in various obvious respects, all without departing fromthe present invention.

DESCRIPTION OF THE INVENTION

[0017] The present invention relates to therapeutic bridged dianilinocompounds and their pharmaceutical compositions and method of usethereof for the prevention and treatment of epilepsies, seizures, andother electroconvulsive disorders. The therapeutic compound comprises acompound having the following formula (I):

[0018] wherein R₁, R₂, R₃, and R₄, are each independently selected fromthe group consisting of hydrogen, hydroxy, amino, phenyl, substituted orunsubstituted C₁₋₁₀ alkyl, C₃₋₁₀ branched alkyl, substituted orunsubstituted C₃₋₈ cycloalkyl, substituted or unsubstituted arylalkyl(comprising Ar—(CH₂)_(n); where Ar is aromatic and n=0-10) substitutedor unsubstituted C₁₋₁₀ alkoxyl, substituted or unsubstituted C₁₋₁₀ acyl,where the substituents are, but are not limited to, substituentsselected from the group consisting of halogen, phenyl, thio, amino,hydroxyl, hydroxylamino, nitrile, carboxyl, amido, phosphate, sulfate,sulfonamide, nitroso, nitrone, azido, imino, hydrazine, guanidino,oxyguanidino, methylguanidino, hydroxyguanidino, aminoguanidino,thioguanidino, amidino, oxyamidino, ureido, thioureido, thioamido, andnitro; and X is selected from the group consisting of —O—, —S—, —N(H)—,—Se—, —Si—, —CH═CH—, —C≡C—, —N═N—, —N═CH—, —CH═N—, —C(S)—, —N(H)S(O)—,—N(H)SO₂—, —N(H)O—, —N(H)S—, —S(O)—, —SO₂—, —PO₄—, —Si(O)—, —C(O)—,—CH₂—, —CF₂—, and a covalent bond

[0019] In an embodiment of the present invention, 4,4′-thiodianiline,4,4′-diaminobenzophenone, 4,4′-methylenedianiline, 4,4′-diaminodiphenylether, and (3-aminophenyl)-(4-aminophenyl) amine are formulated into apharmaceutical preparation comprising the active agent or apharmaceutically acceptable salt or complex thereof and apharmaceutically acceptable carrier.

[0020] It has been discovered that the inventive compositions are usefulin the prevention, palliation, and/or treatment of seizures, conductiondisturbances and electroconvulsive disorders of all types and theirmanifestations irrespective of the origin of the ailment in a subject inneed thereof including humans and other mammals. It is contemplated thatthe inventive compositions can be employed for preventing and/ortreating other conduction disturbances of the central nervous system(CNS), and the emotional, cognitive, and motor symptoms resulting therefrom.

[0021] In an embodiment of the present invention, the inventivecompositions are administered to a subject in need thereof to prevent ortreat disturbances of the CNS, such as seizure and electroconvulsion, ofeither or both an acute or chronic nature, of unknown origin orsecondary to conditions such as, but not limited to: surgery,irradiation, or other manipulation of the brain and/or CNS; alcohol,benzodiazepine, barbiturate or other drug or chemical withdrawal;exposure to epileptogenic drugs and/or chemicals; acute or chronicinjury or trauma; stroke or cerebrovascular accident; fever; meningitisor other CNS inflammation or infection; or electroconvulsive therapy.

[0022] In practicing the present invention, the compound having formula(I) or a pharmaceutically acceptable salt or complex thereof isformulated into pharmaceutical compositions. In an embodiment of thepresent invention, 4,4′-thiodianiline, 4,4′-diaminobenzophenone,4,4′-diaminodiphenyl ether, 4,4′-methylenedianiline, or(3-aminophenyl)-(4-aminophenyl) amine are formulated into pharmaceuticalcompositions

[0023] The compound of formula (I) includes all resolved enantiomers,diastereoisomers, tautomers, salts, solvates and polymorphic formsthereof. Salt forms of 4,4′-thiodianiline, 4,4′-diaminobenzophenone,4,4′-diaminodiphenyl ether, 4,4′-methylenedianiline, or(3-aminophenyl)-(4-aminophenyl) amine include, but are not limited tothe following: inorganic acid addition salts such as hydrochloride,hydrobromide, sulfate, phosphate and nitrate; organic acid additionsalts such as acetate, galactarate, propionate, succinate, lactate,glycolate, malate, tartrate, citrate, maleate, fumarate,methanesulfonate, salicylate, p-toluenesulfonate, benzenesulfonate, andascorbate; salts with acidic amino acids such as aspartate andglutamate; the salts may in some cases by hydrates or solvates withalcohols and other solvents. Salt forms of 4,4′-thiodianiline,4,4′-diaminobenzophenone, 4,4′-methylenedianiline, or(3-aminophenyl)-(4-aminophenyl) amine, can be prepared by mixing theacid in a conventional solvent, with or without alcohols or water.

[0024] The compounds of the present invention are useful inpharmaceutical compositions for systemic administration to mammalsincluding humans as a single agent, or as a primary or adjunct agentwith any other medication, chemical, drug or non-drug therapy, orcombination thereof.

[0025] The aforementioned administration of 4,4′-thiodianiline,4,4′-diaminobenzophenone, 4,4′-methylenedianiline, 4,4′-diaminodiphenylether, or (3-aminophenyl)-(4-aminophenyl) amine, or pharmaceuticallyacceptable salts or complexes thereof is to be employed acutely, or as asingle dose, or administered intermittently, or on a regular schedule ofunspecified duration, or by continuous infusion of unspecified duration,by an acceptable route of administration including, but not limited to,the oral, buccal, intranasal, pulmonary, transdermal, rectal, vaginal,intradermal, intrathecal, intravenous, intramuscular, and/orsubcutaneous routes.

[0026] The pharmaceutical preparations can be employed in unit dosageforms, such as tablets, capsules, pills, powders, granules,suppositories, sterile and parenteral solutions, or suspensions, sterileand non-parenteral solutions or suspensions, oral solutions orsuspensions, oil in water or water in oil emulsions and the like,containing suitable quantities of an active ingredient. Topicalapplication can be in the form of ointments, creams, lotions, jellies,sprays, douches, and the like. For oral administration either solid orfluid unit dosage forms can be prepared with the compounds of Formula I.

[0027] Either fluid or solid unit dosage forms can be readily preparedfor oral administration. For example, the compounds can be mixed withconventional ingredients such as dicalciumphosphate, magnesium aluminumsilicate, magnesium stearate, calcium sulfate, starch, talc, lactose,acacia, methylcellulose and functionally similar materials aspharmaceutical excipients or carriers. A sustained release formulationmay optionally be used. Capsules may be formulated by mixing thecompound with a pharmaceutical diluent which is inert and inserting thismixture into a hard gelatin capsule having the appropriate size. If softcapsules are desired, a slurry (or other dispersion) of the compound,with an acceptable vegetable, light petroleum or other inert oil can beencapsulated by machine into a gelatin capsule.

[0028] Suspensions, syrups, and elixirs may be used for oraladministration of fluid unit dosage forms. A fluid preparation includingoil may be used for oil soluble forms. A vegetable oil, such as cornoil, peanut oil, or safflower oil, for example, together with flavoringagents, sweeteners, and any preservatives produces an acceptable fluidpreparation. A surfactant may be added to water to form syrup for fluiddosages. Hydro-alcoholic pharmaceutical preparations may be used thathave an acceptable sweetener, such as sugar, saccharine, or a biologicalsweetener and a flavoring agent in the form of an elixir.

[0029] Pharmaceutical compositions for parental and suppositoryadministration can also be obtained using techniques standard in theart. Another preferred use of these compounds is in a transdermalparenteral pharmaceutical preparation in a mammal such as a human.

[0030] The above and other drugs can be present in the reservoir alone,or in combination form with pharmaceutical carriers. The pharmaceuticalcarriers acceptable for the purpose of this invention are the art knowncarriers that do not adversely affect the drug, the host, or thematerial comprising the drug delivery device. Suitable pharmaceuticalcarriers include sterile water, saline, dextrose, dextrose in water orsaline, condensation products of castor oil and ethylene oxide combiningabout 30 to about 35 moles of ethylene oxide per mole of castor oil,liquid acid, lower alkanols, oils (such as corn oil, peanut oil, sesameoil and the like), with emulsifiers such as mono- or di-glyceride of afatty acid or a phosphatide (e.g., lecithin and the like), glycols,polyalkyne glycols, aqueous media in the presence of a suspending agent(for example, sodium carboxymethylcellulose), sodium alginate,poly(vinylpyrolidone), and the like (alone or with suitable dispensingagents such as lecithin), or polyoxyethylene stearate and the like. Thecarrier may also contain adjuvants such as preserving, stabilizing,wetting, emulsifying agents and the like together with the penetrationenhancer of this invention.

[0031] By “effective amount,” “therapeutic amount,” “therapeuticeffective amount” or “effective dose” is meant that the amountsufficient to elicit the desired pharmacological or therapeutic effect,thus resulting in effective prevention or treatment of the condition ordisorder. Thus, when treating a CNS disorder, an effective amount ofcompound is that amount sufficient to pass across the blood-brainbarrier of the subject to interact with relevant receptor sites in thebrain of the subject. Prevention of the condition or disorder ismanifested by delaying the onset of the symptoms of the condition ordisorder. Treatment of the condition or disorder is manifested by adecrease in the symptoms associated with the condition or disorder, oran amelioration of the recurrence of the symptoms of the condition ofdisorder.

[0032] The effective dose can vary, depending upon factors such as thecondition of the patient, the severity of the symptoms of the disorder,age, weight, metabolic status, concurrent medications, and the manner inwhich the pharmaceutical composition is administered. Typically, theeffective dose of compounds generally requires administering thecompound in an amount of about 0.1 to 500 mg/kg of the subject's weight.In an embodiment of the present invention, a dose of about 0.1 to about300 mg/kg is administered per day indefinitely or until symptomsassociated with the condition or disorder cease. Preferably, about 1.0to 50 mg/kg body weight is administered per day. The required dose isless when administered parenterally.

EXAMPLE 1 The Maximal Electroshock Seizure (MES) or Maximal SeizurePattern Test

[0033] The MES is an experimental model for generalized tonic-clonicseizures that identifies compounds that prevent seizure spread. The MESmodel is highly reproducible and has a consistent endpoint. An advantageof this model is that the behavioral and electrographic seizures areconsistent with those observed in humans [2].

[0034] In the MES test, the animal receives an electrical stimulus, 0.2seconds in duration, via corneal electrodes primed with an electrolytesolution containing an anesthetic agent. The 0.2 second stimulation isgenerated with 150 mA in rats and 50 mA in mice at 60 Hz. Rats, weighingbetween 105 g and 130 g, and mice, weighing between 18 g and 25.5 g,receive an electrical stimulus 15 minutes, 30 minutes, 1 hour, 2 hours,and 4 hours after administration of the test compound. In rats, thecompound is administered orally, while mice receive the agent viaintraperitoneal injection. The test endpoint, electrogenic seizure, ismanifested as hindlimb tonic extension. Inhibition of hindlimb tonicextension indicates that the test compound is able to inhibitMES-induced seizure spread and therefore may have antiseizure activity[2-4]. The results of the MES test suggest that this class of compoundsis effective in preventing seizure spread in both rats and mice (Tables1 and 2). TABLE 1 Percentage of mice in which 30, 100, or 300 mg/kg ofthe test compound prevented MES-induced seizure 0.5 or 4 hours afterintraperitoneal administration. 0.5 h 4.0 h Test Compound (%) (%)4,4′-thiodianiline  30 mg/kg 0 0 100 mg/kg 66 100 300 mg/kg 100 1004,4′-methylenedianiline  30 mg/kg 0 0 100 mg/kg 100 0 300 mg/kg 100 1004,4′-diaminobenzophenone  30 mg/kg 0 0 100 mg/kg 100 100 300 mg/kg 100100 4,4′-diaminodiphenyl ether  30 mg/kg 0 0 100 mg/kg 100 100 300 mg/kg100 100 (3-aminophenyl)- (4-aminophenyl) amine  30 mg/kg 0 0 100 mg/kg100 100 300 mg/kg 100 100

[0035] TABLE 2 Percentage of rats in which 30 mg/kg of the test compoundprevented MES-induced seizure 0.25, 0.5, 1.0, 2.0 or 4.0 hours afteroral administration. Test Compound 0.25 h 0.5 h 1.0 h 2.0 h 4.0 h (30mg/kg) (%) (%) (%) (%) (%) 4,4′-thiodianiline 100 100 100 100 1004,4′-methylenedianiline 100 75 92 100 50 4,4′-diaminobenzophenone 50 10075 100 75 4,4′-diaminodiphenyl ether 100 100 75 75 100 (3-aminophenyl)-0 50 75 50 50 (4-aminophenyl) amine

[0036] A full dose-response curve was also generated in rats todetermine the ED₅₀ value (n=8 at each time point). These experimentswere conducted at the compound's time of peak pharmacodynamic activityand the results are shown in Table 3. 4,4′-Diaminodiphenyl ether was themost active compound (ED₅₀: 5.24±4.67 mg/kg) and also had the longesttime to peak effect (6 hours). The ED₅₀ of 4,4′-thiodianiline wasevaluated in both rats and mice. In rats, 1 hour after oraladministration, 4,4′-thiodianiline had an ED₅₀ of 6.60±5.07 mg/kg, and0.5 hours after intraperitoneal administration in mice it had an ED₅₀ of53.42±14.92 mg/kg. TABLE 3 ED₅₀ required to inhibited MES-inducedseizure at the time of peak effect in rat after oral administration ofthe test compound Time to Peak Effect ED₅₀ Test Compound (hours) (mg/kg)4,4′-thiodianiline 1 6.60 ± 5.07 4,4′-methylenedianiline 1 10.63 ± 5.88 4,4′-diaminobenzophenone 1 7.15 ± 1.89 4,4′-diaminodiphenyl ether 6 5.24± 4.67 (3-aminophenyl)- 2 31.74 ± 24.42 (4-aminophenyl) amine

EXAMPLE 2 6 Hz Kindling Model

[0037] The 6 Hz kindling model is another experimental seizure modelthat effectively detects compounds with anti-seizure activity. Thisscreen is used to evaluate the ability of a compound to prevent theacquisition of focal seizures; in particular, the capacity of a compoundto prevent the development of seizures induced by a low-frequency (6Hz), long duration (three seconds) stimulus in electrode implanted ratsis evaluated [5]. Several of the most promising compounds were evaluatedin this screen to further characterize their anti-seizure activity.

[0038] In the 6 Hz kindling test, mice are implanted with cornealelectrodes. The test compound is administered (i.p.) to the animal at0.25, 0.5, 1, 2, or 4 hours prior seizure induction. The seizure isinitiated by delivering a current (32 mA at 6 Hz for three seconds) tothe animal through the corneal electrodes. The resulting psychomotorseizure is usually characterized by a minimal clonic phase followed bystereotyped, automatistic behaviors. This response is analogous to theaura of human patients with partial seizures. If the animal does notexhibit this behavior, the test compound is considered to have protectedthe animal and have anti-seizure properties.

[0039] The data in Table 4 clearly indicates the capacity of4,4′-thiodianiline, 4,4′-diaminobenzophenone, and4,4′-methylenedianiline to inhibit 6 Hz seizures. 4,4′-Thiodianiline wasthe most effective compound evaluated, having an ED₅₀ value between 30and 80 mg/kg. At a dose of 100 mg/kg, all four of the compounds testedinhibited seizure in 100% of the animals tested 0.25, 0.5 and 1.0 hoursafter administration of the compound. TABLE 4 Percentage of Mice inwhich Exposure to the Test Compound Prevented Seizure in the 6 Hz Testat 0.25, 0.5, 1.0, 2.0 and 4.0 Hours after intraperitonealAdministration 0.25 h 0.5 h 1.0 h 2.0 h 4.0 h Test Compound (%) (%) (%)(%) (%) 4,4′-thiodianiline  30 mg/kg 0 25 25 25 ND  80 mg/kg 100 100 10075 0 100 mg/kg 100 100 100 100 0 4,4′-diaminobenzophenone  30 mg/kg 0 00 ND ND 100 mg/kg 100 100 100 0 0 4,4′-diaminodiphenyl ether  30 mg/kg 050 25 25 ND 100 mg/kg 100 100 100 100 0 4,4′-methylenedianiline  30mg/kg 0 0 0 ND ND 100 mg/kg 100 100 100 0 0

EXAMPLE 3 Hippocampal Kindling Model

[0040] The hippocampal kindling model is an experimental seizure modelused to simulate focal seizures. This model evaluates the capacity of acompound to affect both the expression and acquisition of focalseizures. In addition, kindled seizures provide a methodology forstudying complex brain networks that may contribute to the spread andgeneralizations of seizures from a focus. The hippocampal kindling modelhas the advantage of being one of the only kindling models that canevaluate the temporal effects of an agent in a single animal [6,7]. Forthis assessment, bipolar electrodes are surgically implanted in theventral hippocampus of adult male Sprague-Dawley rats (275-300 g) underketamine-xylazine anesthesia. Following a one-week recovery period,stage five behavioral seizures are induced by stimulating the rat 12times per day with 50 Hz, 10 s train of 1 ms biphasic 200 μA pulsesdelivered every 30 min for six hours on alternating days. After fivestimulus days, the animal has had 60 stimulations. A drug free controlperiod with supramaximal stimulations is used to verify the stability ofa stage five generalized seizure before the anticonvulsant activity of adrug is measured.

[0041] This screen is used to measure the capacity of the drug toprevent the expression of focal seizures. During a drug trial, theafterdischarge threshold of each animal is determined by increasing thecurrent intensity, stepwise, until the rat displays an electrographicafterdischarge lasting at least four seconds. The animal is exposed toan initial stimulation of 20 μA; the stimulation is increased in 10 μAincrements every one-two minutes until an afterdischarge is recorded.After the stability of the stage five seizure is established, the drugcandidate is administered to the rats via intraperitoneal injection 15minutes after the last control stimulation. Starting with the firstdose, the anticonvulsant activity of the test agent is measured everythirty minutes for four hours. Following each stimulation, Racineseizure scores and afterdischarge durations [8] are compared to controlvalues to quantify the anti-convulsant activity of the agent. The Racineseizure scores vary from stage 1 to 5. The stages are characterizedaccording to the following criteria: Stage 1—mouth and facial clonus,Stage 2—stage 1 and head nodding, Stage 3—stage 2 and forelimb clonus,Stage 4—stage 3 and rearing, Stage 5—stage 4 and repeated rearing andfalling [8]. Since a single animal is used, each rat serves as its owncontrol.

[0042] 4,4′-Thiodianiline was used in the rat hippocampal kindled ratsto screen to measure its anticonvulsant potential. Doses of 12.5, 25, 50and 100 mg/kg were evaluated at a minimum of seven time points (n=7 foreach dose and each time point). Table 5 shows the raw data from a 100mg/kg dose of 4,4′-thiodianiline. After oral administration of the testcompound stimulation, the Racine seizure scores and afterdischargedurations were measured and are shown below. The Racine seizure scoresdropped from between a stage 4 and stage 5 seizure for controlmeasurements to between a stage 1 and stage 2 seizure after treatmentwith 4,4′-thiodianiline. TABLE 5 Racine Seizure Scores andAfterdischarge Durations Following Stimulation, for Rats Treated with100 mg/kg of 4,4′-Thiodianiline. Racine Seizure Afterdischarge DurationTime (mm) Score ± SEM (sec) ± SEM Control 4.86 ± 0.14  72.57 ± 7.20   151.43 ± 0.81* 19.14 ± 9.58*   45 1.29 ± 0.84* 25.29 ± 13.71*  75 0.71 ±0.57* 24.86 ± 11.43* 105 1.29 ± 0.64* 33.29 ± 14.17* 135 1.57 ± 0.81*34.71 ± 14.35* 165 1.57 ± 0.65* 57.43 ± 18.17  195 1.57 ± 0.69* 55.29 ±18.19  225 1.86 ± 0.70* 71.29 ± 18.99  255 1.86 ± 0.63* 65.43 ± 17.91 

[0043] Using the data generated from each of the doses,4,4′-thiodianiline, was found to have an ED₅₀ of 51.43 mg/kg. This isthe dose of 4,4′-thiodianiline required to prevent the expression offocal seizures in this model. The capacity of 4,4′-thiodianiline toelevate afterdischarge threshold and decrease afterdischarge durationsuggests that it possess the ability to limit focal seizure activityoriginating from the ventral hippocampus.

[0044] 4,4′-Diaminobenzanalide and 4,4′-diaminodiphenyl ether were alsoevaluated in the hippocampal kindling model. While these compounds werenot as effective as 4,4′-thiodianiline, they also had the capacity toblock the expression of fully kindled seizures.

EXAMPLE 4 Minimal Neurotoxicity

[0045] Toxicity in mice and rats is assessed using three screens: therotorod in mice, positional sense and gait in rats. In mice, the testcompound is administered at doses of 30, and 100 mg/kg prior toevaluation in the toxicity screens. The mice are tested at 0.5 hours and4 hours after intraperitoneal administration of the test compound. Inrats, the test compound is administered at 30 mg/kg prior to thetoxicity assessment. The rats are tested at 0.25, 0.5, 1, 2, and 4 hoursafter oral administration of the test compound. In rats, a series ofdoses were tested at the time to peak effect to determine the toxicityED₅₀ at this timepoint.

Rotorod Test

[0046] Toxicity in mice weighing between 18 and 25.5 g is assessed usingthe standardized rotorod test [9]. For each compound tested, a minimumof 18 animals are evaluated for neurotoxicity. Control mice can maintaintheir equilibrium for an extended period of time when they are placed ona 6-rpm rotation rod. Neurologically impaired animals cannot maintainequilibrium for one minute in each of three successive trials.

Positional Sense Test

[0047] Behavioral toxicity in twenty rats weighing between 105 and 130 gis assessed by the positional sense test. In this test, one hind leg isgently lowered over the edge of a table. If the rat experiencesneurological toxicity, it will not be able to quickly lift its legquickly back to a normal position.

Gait and Stance Test

[0048] In the gait and stance test, neurotoxicity is indicated by acircular or zigzag gait after administration of the test compound. Inaddition, ataxia, abnormal spread of the legs, abnormal posture, tremorhyperactivity, lack of exploratory behavior, somnolence, stupor, orcatalepsy can indicate neurotoxicity. This toxicity test was conductedon rats, weighing between 105 and 130 g.

[0049] The acute neurotoxicity of this class of compounds was shown tobe well above the doses required for therapeutic benefit. No acuteneurotoxicity was observed as measured by the rotorod test up to fourhours after mice had been given 4,4′-thiodianiline, even at doses ashigh as 300 mg/kg. In rats, 1 hour (the time to peak effect) after oraladministration of 4,4′-thiodianiline, the ED₅₀ for toxicity wasdetermined to be almost 60 times greater than the ED₅₀ foranti-convulsant activity. Similarly, 4,4′-diaminobenzophenone was notneurotoxic to rats. None of the rats tested at any timepoints (0.25 to24 hours after oral administration of 4,4′-diaminobenzophenone) showedacute neurotoxic effects, even at doses as high as 500 mg/kg. Incontrast, the ED₅₀ for anti-convulsant activity for4,4′-diaminobenzophenone in rats was 7.15 mg/kg. In mice,4,4′-diaminobenzophenone showed no neurotoxicity at doses below 100mg/kg. 4,4′-Diaminodiphenyl ether, 4,4′-methylenedianiline and(3-aminophenyl)-(4-aminophenyl) amine had no significant toxicity evenat 100 mg/kg in mice and 250 mg/kg in rats.

[0050] These data suggest that the acute neurotoxicity levels of thesecompounds in mice and rats, as assessed by the rotorod test, thepositional sense and the gait and stance tests, far exceed the levelrequired for anticonvulsant activity.

REFERENCES

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[0052] 2. Levy, R. H., Antiepileptic drugs. 3rd/ed. 1989, New York:Raven Press. xxvii, 1025.

[0053] 3. Levy, R. H., R. H. Mattson, and B. S. Meldrum, Antiepilepticdrugs. 4th/ed. 1995, New York: Raven Press. xxv, 1120.

[0054] 4. White, H. S., M. Johnson, H. H. Wolf, and H. J. Kupferberg.(1995) The early identification of anticonvulsant activity: role of themaximal electroshock and subcutaneous pentylenetetrazol seizure models.Ital J Neurol Sci 16:73-7.

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[0060] While the salient features have been illustrated and describedwith respect to particular embodiments, it should be readily apparentthat modifications can be made within the spirit and scope of theinvention, and it is therefore not desired to limit the invention to theexact details shown and described.

1. A therapeutic compound, including resolved enantiomers,diastereoisomers, tautomers, salts, solvates and polymorphic formsthereof, having the following formula (I):

wherein R₁, R₂, R₃, and R₄, are each independently selected from thegroup consisting of hydrogen, hydroxy, amino, phenyl, a substituted orunsubstituted C₁₋₁₀ alkyl, C₃₋₁₀ branched alkyl, a substituted orunsubstituted C₃₋₈ cycloalkyl, a substituted or unsubstituted arylalkyl,a substituted or unsubstituted C₁₋₁₀ alkoxyl and a substituted orunsubstituted C₁₋₁₀ acyl; and X is selected from the group consisting of—O—, —S—, —N(H)—, —Se—, —Si—, —CH═CH—, —C≡C—, —N═N—, —N═CH—, —CH═N—,—C(S)—, —N(H)S(O)—, —N(H)SO₂—, —N(H)O—, —N(H)S—, —S(O)—, —SO₂—, —PO₄—,—Si(O)—, —C(O)—, —CH₂—, —CF₂—, and a covalent bond; with the provisothat R₁, R₂, R₃, and R₄ are not hydrogen when X is oxygen.
 2. Thecompound of claim 1, wherein the substituted or unsubstituted arylalkylcomprises Ar—(CH₂)_(n); where Ar is an aromatic ring and n is from 1 to10.
 3. The compound of claim 2, wherein the substituents of thesubstituted groups are selected from the group consisting of halogen,phenyl, thio, amino, hydroxyl, hydroxylamino, nitrile, carboxyl, amido,phosphate, sulfate, sulfonamide, nitroso, nitrone, azido, imino,hydrazine, guanidino, oxyguanidino, methylguanidino, hydroxyguanidino,aminoguanidino, thioguanidino, amidino, oxyamidino, ureido, thioureido,thioamido and nitro.
 4. The compound of claim 1, wherein the compound isselected form the group consisting of 4,4′-thiodianiline,4,4′-diaminobenzophenone, 4,4′-diaminodiphenyl ether,4,4′-methylenedianiline, and (3-aminophenyl)-(4-aminophenyl) amine. 5.The compound of claim 1, wherein the compound is 4,4′-thiodianiline. 6.The compound of claim 1, wherein the compound is4,4′-diaminobenzophenone. 7 (canceled).
 8. The compound of claim 1,wherein the compound is 4,4′-methylenedianiline.
 9. The compound ofclaim 1, wherein the compound is (3-aminophenyl)-(4-aminophenyl) amine.10. A pharmaceutical composition comprising the compound of claim 1 inan admixture with a pharmaceutically acceptable carrier, adjuvant orvehicle.
 11. A pharmaceutical composition comprising the compound ofclaim 3 in an admixture with a pharmaceutically acceptable carrier,adjuvant or vehicle.
 12. A pharmaceutical composition comprising thecompound of claim 4 in an admixture with a pharmaceutically acceptablecarrier, adjuvant or vehicle.
 13. A pharmaceutical compositioncomprising the compound of claim 5 in an admixture with apharmaceutically acceptable carrier, adjuvant or vehicle.
 14. Apharmaceutical composition comprising the compound of claim 6 in anadmixture with a pharmaceutically acceptable carrier, adjuvant orvehicle.
 15. A pharmaceutical composition comprising the compound ofclaim 7 in an admixture with a pharmaceutically acceptable carrier,adjuvant or vehicle.
 16. A pharmaceutical composition comprising thecompound of claim 8 in an admixture with a pharmaceutically acceptablecarrier, adjuvant or vehicle.
 17. A pharmaceutical compositioncomprising the compound of claim 9 in an admixture with apharmaceutically acceptable carrier, adjuvant or vehicle.
 18. A methodof treating, ameliorating, or preventing epilepsy, seizure orelectroconvulsive disorders in mammals which comprises administering atherapeutic effective amount of the compound of claim 1 to said mammal.19. A method of treating, ameliorating, or preventing epilepsy, seizureor electroconvulsive disorders in mammals which comprises administeringa therapeutic effective amount of the compound of claim 1 to saidmammal.
 20. A method of treating, ameliorating, or preventing epilepsy,seizure or electroconvulsive disorders in mammals which comprisesadministering a therapeutic effective amount of the compound of claim 3to said mammal.
 21. A method of treating, ameliorating, or preventingepilepsy, seizure or electroconvulsive disorders in mammals whichcomprises administering a therapeutic effective amount of the compoundof claim 4 to said mammal.
 22. A method of treating, ameliorating, orpreventing epilepsy, seizure or electroconvulsive disorders in mammalswhich comprises administering a therapeutic effective amount of thecompound of claim 5 to said mammal.
 23. A method of treating,ameliorating, or preventing epilepsy, seizure or electroconvulsivedisorders in mammals which comprises administering a therapeuticeffective amount of the compound of claim 6 to said mammal.
 24. A methodof treating, ameliorating, or preventing epilepsy, seizure orelectroconvulsive disorders in mammals which comprises administering atherapeutic effective amount of the compound of claim 7 to said mammal.25. A method of treating, ameliorating, or preventing epilepsy, seizureor electroconvulsive disorders in mammals which comprises administeringa therapeutic effective amount of the compound of claim 8 to saidmammal.
 26. A method of treating, ameliorating, or preventing epilepsy,seizure or electroconvulsive disorders in mammals which comprisesadministering a therapeutic effective amount of the compound of claim 9to said mammal.
 27. The method of claim 21, wherein the therapeuticeffective amount is from about 0.1 mg/kg to about 300 mg/kg.
 28. Themethod of claim 21, wherein the therapeutic effective amount is fromabout 1 mg/kg to about 40 mg/kg.